In this project the specific objectives are to define the unique epidemiologic, clinical, virologic, and immunologic features of HIV infection in developing countries; to determine the viral kinetics associated with perinatal and heterosexual transmission, and to characterize the molecular strains of HIV throughout the world for infectiousness and the immunologic response to cross-clade vaccines. In collaborative studies we have established cohorts of high-risk individuals in Uganda, Congo, Zambia, Zimbabwe, South Africa, India, China and the U.S. In these cohorts we have characterized the prevalence, incidence, and risk behaviors for HIV infection. In the Rakai district of Uganda we estimated the HIV acquisition rate per coital act among 218 HIV-discordant monogamous couples. The acquisition rate of HIV was 0.0011/act and did not vary significantly by gender, age, pregnancy status, hormonal contraception, reported condom use, or STD diagnosis. Acquisition was significantly associated with current genital ulcer disease in women. No seroconversions occurred among men circumcised at baseline vs. a rate of 0.0013 per act among uncircumcised men. Acquisition increased significantly with higher HIV viral load in the infected partner (0.0001/act < 1700 copies/ml vs. 0.0022/act at > 38,500 copies/ml). HIV acquisition was also associated with HSV-2 seropositivity with an odds ratio of 2.6. In addition, at 5 months post-seroconversion viral load was significantly greater in HSV-2 seropositive compared to HSV-2 seronegative individuals. Thus, HSV-2 infection is associated with HIV acquisition and this interaction of HSV-2 and HIV with subsequent increased viral loads among herpes-positive individuals supports the need for HSV-2 treatment and prophylaxis in infected individuals. Utilizing these Rakai data, we developed a stochastic simulation model to determine the effect of antiretroviral therapy or vaccines in the reduction of HIV incidence in developing countries. Using DHHS treatment guidelines in the model, antiretroviral therapy alone will have a negligible effect on the spread of the epidemic, although it will provide beneficial effects in many other ways for the individual and the population. In contrast, a preventative vaccine, or a therapeutic vaccine that reduces viral load will dramatically reduce HIV transmission and HIV incidence. However, increased risk behaviors would markedly offset these benefits. In order to determine whether the early immunologic and virologic events of HIV infection are unique in a setting with limited access to health care and HIV-1 subtype C infection, we undertook a prospective cohort study to characterize the early natural history of HIV viral load and CD4+ T lymphocyte counts in individuals with recent HIV seroconversion in India. The median viral set-point for Indian seroconverters was 28,729 copies/ml. The median CD4+ T cell count following acute primary infection was 644 cells/ml3. Over the first two years since primary infection, the annual rate of increase in HIV viral load was +8274 RNA copies/ml per year and the annual decline in CD4+ T cell count was ?120 cells/ml3/yr. Although the viral set-point was similar, the median trajectory of increasing viral load in Indian seroconverters was greater than what has been reported in untreated HIV seroconverters in the U.S. These data suggest that the more rapid HIV disease progression described in resource-poor settings may be due to very early virologic and host events following primary HIV infection. In preliminary studies we demonstrated that HIV-1 B/C from the West and A/E from the South are spreading throughout southern China. In studying IDUs in the cities of Pinjxiang and Binyang, the HIV prevalence was 25% and 19% with incident rates of 5.2 and 8.0/100 py, respectively. HIV viral loads were similar by subtype and region. Sequence analysis of the gag-pol region and the C2-V4 env region showed that 93% of the infections in Pinjxiang were A/E while 96% in Binyang were B/C. Greater diversity of the viral sequences was demonstrated in the B/C-infected subjects than those with A/E. Epidemiologic data support different mechanisms for the spread of HIV with multiple introductions of the A/E epidemic into the Pinjxiang and greater spread through sexual transmission, resulting in greater variation in V3. The significance of these studies is that they provide important epidemiologic, clinical, virologic, and immunologic knowledge of HIV infection in developing countries, which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.